Cyrus Eduljee

Bio: Cyrus Eduljee is an academic researcher. The author has contributed to research in topics: Voltage-dependent calcium channel & T-type calcium channel. The author has an hindex of 5, co-authored 6 publications receiving 372 citations.

T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures

Abstract: Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.

Analgesic Effects of a Substituted N-Triazole Oxindole (TROX-1), a State-Dependent, Voltage-Gated Calcium Channel 2 Blocker

Abstract: Voltage-gated calcium channel (Ca v )2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca v 2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N -triazole oxindole, (3 R )-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1 H -1,2,4-triazol-3-yl)-1,3-dihydro-2 H -indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca v 2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca v 2.2 channels under depolarized conditions (IC 50 = 0.27 μM) compared with hyperpolarized conditions (IC 50 > 20 μM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited ω-conotoxin GVIA-sensitive calcium currents (Ca v 2.2 channel currents), with greater potency under depolarized conditions (IC 50 = 0.4 μM) than under hyperpolarized conditions (IC 50 = 2.6 μM), indicating state-dependent Ca v 2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca v 2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca v 2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca v 2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca v 2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.

A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain

Abstract: Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including NaV1.7 and NaV1.8 sodium channels and CaV3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.

Characterization of the Substituted N-triazole oxindole, TROX-1, a Small Molecule, State-dependent Inhibitor of CaV2 Calcium Channels

Abstract: Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca V 2.2) as therapeutic targets for chronic pain. A state-dependent Ca V 2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca V 2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent Ca V 2 inhibitor (3 R )-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1 H -1,2,4-triazol-3-yl)-1,3-dihydro-2 H -indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits Ca V 2.2 channels with an IC 50 of 0.11 μM. The voltage dependence of Ca V 2.2 inhibition was examined using automated electrophysiology. TROX-1 IC 50 values were 4.2, 0.90, and 0.36 μM at −110, −90, and −70 mV, respectively. TROX-1 displayed use-dependent inhibition of Ca V 2.2 with a 10-fold IC 50 separation between first (27 μM) and last (2.7 μM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited Ca V 2.2 channels with an IC 50 of 9.5 μM under hyperpolarized conditions and 0.69 μM under depolarized conditions. Finally, TROX-1 potency was examined across the Ca V 2 subfamily. Depolarized IC 50 values were 0.29, 0.19, and 0.28 μM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 μM by calcium influx for Ca V 2.1, Ca V 2.2, and Ca V 2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non–subtype-selective Ca V 2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent Ca V 2.2-selective inhibitor ziconotide in preclinical models of chronic pain.

A fluorescence-based high-throughput screening assay for the identification of T-type calcium channel blockers.

Abstract: T-type voltage-gated Ca2+ channels have been implicated in contributing to a broad variety of human disorders, including pain, epilepsy, sleep disturbances, cardiac arrhythmias, and certain types of cancer. However, potent and selective T-type Ca2+ channel modulators are not yet available for clinical use. This may in part be due to their unique biophysical properties that have delayed the development of high-throughput screening (HTS) assays for identifying blockers. One notable challenge is that at the normal resting membrane potential (Vm) of cell lines commonly utilized for drug screening purposes, T-type Ca2+ channels are largely inactivated and thus cannot be supported by typical formats of functional HTS assays to both evoke and quantify the Ca2+ channel signal. Here we describe a simple method that can successfully support a fluorescence-based functional assay for compounds that modulate T-type Ca2+channels. The assay functions by exploiting the pore-forming properties of gramicidin to control the...

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Abstract: Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.

Conus Venom Peptide Pharmacology

Abstract: Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies.

Regulating excitability of peripheral afferents: emerging ion channel targets.

Abstract: The transmission and processing of pain signals relies critically on the activities of ion channels that are expressed in afferent pain fibers. This includes voltage-gated channels, as well as background (or leak) channels that collectively regulate resting membrane potential and action potential firing properties. Dysregulated ion channel expression in response to nerve injury and inflammation results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain. Pharmacological modulators of ion channels, particularly those that target channels on peripheral neurons, are being pursued as possible analgesics. Over the past few years, a number of different types of ion channels have been implicated in afferent pain signaling. Here we give an overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain.

Targeting voltage-gated calcium channels in neurological and psychiatric diseases

Abstract: Voltage-gated calcium channels are important regulators of brain, heart and muscle functions, and their dysfunction can give rise to pathophysiological conditions ranging from cardiovascular disorders to neurological and psychiatric conditions such as epilepsy, pain and autism. In the nervous system, calcium channel blockers have been used successfully to treat absence seizures, and are emerging as potential therapeutic avenues for pathologies such as pain, Parkinson disease, addiction and anxiety. This Review provides an overview of calcium channels as drug targets for nervous system disorders, and discusses potential challenges and opportunities for the development of new clinically effective calcium channel inhibitors.